The role of Fbxw7 in genetic instability and cancer development ABSTRACT Genetic instability is one of the hallmarks of human cancers, particularly in the most common tumors of epithelial origin. The p53 gene is a tumor suppressor with an essential role in induction of growth arrest and apoptosis in response to DNA damage, and is involved in protection from genomic instability. The Fbxw7 gene is a direct transcriptional target of p53 that undergoes deletions and mutations in mouse lymphomas in a p53-dependent manner. Loss of the human FBXW7 gene also leads to genetic instability, and mutations have been detected in cancers from a wide spectrum of human tissues, such as bile duct, blood, bone, brain, breast, colon, endometrium, stomach, lung, ovary, pancreas, and prostate. Alteration of the Fbxw7 gene results in impaired degradation of multiple targets and their consequent accumulation, which may cooperatively contribute to tumor development. However it still remains largely unclear which target is most related to cancer development in Fbxw7-mutant cancer cells. The goal of the first aim is to investigate Fbxw7- mTOR pathway in cancer development. Our preliminary results have shown that mTOR is a new target of Fbxw7, and preliminary genetic analysis of gene copy number changes in human breast cancers gave rise to the intriguing possibility that deletions of FBXW7 and PTEN may be mutually exclusive. We will investigate whether mTOR is required for tumor development in Fbxw7-depelition cells and whether tumors harboring the alteration of Fbxw7 or Pten are sensitive to mTOR inhibitor, such as Rapamycin, treatment. In aim 2, we will elucidate the role of Fbxw7-Aurora-A in genomic instability and tumor development. We will investigate the functional relationship between Fbxw7 and Aurora-A kinase in control of chromosome segregation and aneuploidy, both in vitro and in vivo. In aim 3, we have demonstrated that a functional strain-dependent polymorphism in the N-terminus of Fbxw7 affects the activity of the protein, and influences susceptibility to lymphoma development. We will elucidate the mechanism of action of this genetic variant and determine its role in tumor susceptibility. Therefore we anticipate this project will address critically important questions related to the role of Fbxw7 in tumor development and tumor susceptibility, and possible clinical implications in the therapy of human cancer harboring alteration of FBXW7. PUBLIC RELEVANCE: FBXW7 is emerging as a major human tumor suppressor gene that has been mutated in cancers from a wide spectrum of human tissues, such as bile duct, blood, bone, brain, breast, colon, endometrium, stomach, lung, ovary, pancreas, and prostate. The understanding of the role of FBXW7 in tumor development and tumor susceptibility may provide novel preventive or therapeutic possibilities for many human cancers. 1 [unreadable] [unreadable] [unreadable] [unreadable]